Trauma to the brain or spinal cord caused by physical forces acting on the skull or spinal column, by ischemic stroke, arrested breathing, cardiac arrest, Reye's syndrome, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, encephalomyelitis, hydrocephalus, post-operative brain injury, cerebral infections and various concussions results in edema and swelling of the affected tissues. This is followed by ischemia, hypoxia, necrosis, temporary or permanent brain and/or spinal cord injury and may result in death. The tissue mainly affected are classified as grey matter, more specifically astroglial cells. The specific therapy currently used for the treatment of the medical problems described include various kinds of diuretics (particularly osmotic diuretics), steroids (such as, 6-.alpha.-methylprednisolone succinate) and barbiturates. The usefulness of these agents is questionable and they are associated with a variety of untoward complications and side effects. Thus, the compounds of this invention comprise a novel and specific treatment of medical problems where no specific therapy is available.
A recent publication entitled "Agents for the Treatment of Brain Injury" 1. (Aryloxy)alkanoic Acids, Cragoe et al., J. Med. Chem., (1982) 25, 567-79, reports on recent experimental testing of agents for treatment of brain injury and reviews the current status of treatment of brain injury.
Some compounds having structures related to the compounds of the present invention have been reported to be diuretic and saluretic agents in Cragoe U.S. Pat. Nos. 4,070,539 and 4,249,021. Additionally, Williams, H. W. R. et al., J. Org. Chem., 44, 4060 (1979) reported that the ether linkage in [(6,7-dichloro-1-oxo-5-indanyl)oxy]acetic acids could be substituted by nitrogen under strongly basic conditions. There is, however, no suggestion in the patents or publication that any of the compounds disclosed therein would be of use in the treatment of brain injury.
The compounds of the invention have the added advantage of being devoid of the pharmacodynamic, toxic or various side effects characteristic of the diuretics, steroids and barbiturates.